Unit 13

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Unit 13: B lymphocyte activation

The activation of B lymphocytes is different for the various types of existing B lymphocytes. Remember that
there are three types of virgin B lymphocytes, B lymphocytes 2F (follicular), B 1 and B 2ZM (marginal zone
of the spleen):
- 2F B lymphocytes: they are the most abundant. They have very diverse B-cell receptors (BCRs). They are
located in the follicles of the ganglia, spleen and mucosa-associated lymphoid tissues (MALT). As 2F B
lymphocytes account for 90% of all B lymphocytes, when we talk about B lymphocytes generically, we
refer to them.
- B lymphocytes 1 and B 2ZM : are rare. They have little diverse BCR. B 1 lymphocytes are found in the
pleural, peritoneal and pericardial cavities and 2ZM B lymphocytes in the marginal zone of the spleen.
The activation of B lymphocytes is carried out in two phases that serve a series of objectives. The first phase
is common to all types of B lymphocytes, while the second is specific to 2F B lymphocytes: in the first phase
of activation, B lymphocytes perform clonal expansion, antibody secretion and differentiation to plasma
cells. In the second phase, memory B lymphocytes are generated. The 2F B lymphocytes are the only ones
that reach the second phase and, therefore, only they generate memory B lymphocytes.
Exposed in detail, the activation of 2F B lymphocytes develops as follows:

- In the first phase:


o Antigen uptake and migration of 2F B lymphocytes, and activation and migration of HF (Follicular
helper T) T lymphocytes.
o Interaction between 2F and HF T B lymphocytes.
o Clonal expansion and differentiation of 2F B lymphocytes.
- In the second phase:
o Formation of the germinal center. In this region happens the last phase of maturation of 2F B
lymphocytes, which leads to an improvement of antibodies in two aspects: improvement of
affinity and improvement of isotype.
o Generation of plasma cells and memory B lymphocytes.

The details of B1 and B 2ZM cell activation will be described at the end of the chapter.

FIRST PHASE OF ACTIVATION OF 2F B LYMPHOCYTES


Remember that, unless otherwise indicated, the name B lymphocytes refers in this section to 2F B
lymphocytes.

Antigen uptake by 2F B lymphocytes


The antigens that B lymphocytes capture come from a pathogen that penetrates through the skin or
mucous membranes. Because these antigens are soluble, they are picked up by lymphatic vessels from the
input tissues and carried to the nearest node. In the ganglion, antigens are taken up directly or indirectly by
B lymphocytes. In the latter case, macrophages of the subcapsular sinus have the ability to capture
antigens, keep them on the cell surface and transport them to B
lymphocytes.

First phase of activation of 2F B lymphocytes.


(a) B lymphocytes (LB) take up soluble antigens (Ag) that reach the ganglion. (b) LBs endocyte
Ag, process it, and present it via HLA. (c) Dendritic cells (DC) present Ag to T lymphocytes (LT)
and induce clonal expansion and differentiation to HF T. (d) HF T activates the LBs that present
them with the antigen. (e) LBs perform extrafollicular clonal expansion. (f) Some differentiate
into plasma cells. (g) Both LBs and plasma cells produce antibodies; Plasma cells and antibodies
exit the node through the efferent lymph vessel.
B lymphocytes recognize the antigen with their BCR. They then endocyte the BCR-antigen complex, process
it and present it via the HLA-II antigen presentation pathway (fig. 13.1b). As a result, B lymphocytes migrate
within the follicle to the so-called interphase region, bordering the paracortical region.
Simultaneously, dendritic cells take up the pathogen or fragments of it in the same input tissues and, as a
consequence, mature and migrate through the lymphatic route to the same ganglion. In the paracortical
zone of the ganglion they activate T lymphocytes and induce their clonal expansion and differentiation to
HF T.
Activation of B lymphocytes by collaboration with HF T lymphocytes
While B lymphocytes migrate to the paracortical zone, HF T cells migrate to the follicle. Both cells will
eventually be found in the interphase region. HF T cells then interact with and activate B cells through the
following events:
- B lymphocytes present the antigen via HLA-II to HF T lymphocytes.
- HF T cells recognize the antigen through their TCR (T-cell receptor) and activate B lymphocytes through
the effector molecule CD40L (CD40 ligand).
It should be noted that the involvement of dendritic cells in the process of activation of B lymphocytes is
the way that the innate immune system has to warn B lymphocytes of the adaptive immune system:
dendritic cells activate T lymphocytes so that they differentiate into HF T lymphocytes and these, in turn,
will activate B lymphocytes.

Clonal expansion and differentiation


As a consequence of the activation of B lymphocytes in the first phase there is an extrafollicular clonal
expansion. B cell clones secrete antibodies. Some B lymphocytes differentiate into plasma cells. Both B
lymphocytes and plasma cells secrete antibodies of the majority IgM isotype. Plasma cells secrete IgM in
greater abundance than B lymphocytes.
With the formation of antibodies the effector phase of B lymphocytes is reached, since the function of
antibodies is to eliminate the pathogen. To do this, antibodies recognize the antigen, bind to it and induce
different processes. In the case of IgM they can:
- Neutralize the antigen. They do this by binding the antibody to the antigen to prevent the antigen from
harming the body, as would happen for example with toxins.
- Activate the add-in. Once activated, complement can opsonize the pathogen for phagocytosis or it can
create pores on the surface of the pathogen.

SECOND PHASE OF ACTIVATION OF B LYMPHOCYTES. FORMATION OF THE GERMINAL CENTER


This phase takes place in the follicular zone of the ganglia. B lymphocytes undergo extensive proliferation
and, simultaneously, a maturation process. During maturation, B lymphocytes change the BCR isotype
towards the most convenient and specific against the pathogen. At the same time, BCRs improve their
affinity through the affinity maturation process. Finally, mature B lymphocytes differentiate into plasma
cells and memory B lymphocytes. Below, we will explain these stages in more detail.
First, after the first activation phase, some of the B lymphocytes that performed clonal expansion in the
interphase zone return to the follicle along with HF T cells. These B lymphocytes continue their clonal
expansion in the follicle with the collaboration of HF T lymphocytes. The region of the follicle where this
extensive proliferation occurs is called the germinal center. In the germinal center two regions are
distinguished:

- The dark zone. It contains abundant B lymphocytes and some HF T. B lymphocytes are continuously
proliferating with the help of HF T lymphocytes.
- The clear zone: contains B lymphocytes and follicular dendritic cells.
Second phase of activation of 2F B lymphocytes.
(a) Some activated B lymphocytes (LB) in the
extrafollicular region return to the follicle. (b)
They form the germinal center, where clonal
expansion continues. (c) In the germinal center,
LBs mature with the collaboration of HF T
lymphocytes (LT HF) and follicular dendritic cells
(DC F). (d) After maturing, LBs differentiate into
memory LBs (LB M) and long-lived plasma cells.
(e) Both LB M and plasma cells leave the ganglion
and secrete antibodies (Ac).

The formation of the germinal center manifests clinically with inflammation of the lymph nodes. To get to
this point there have previously been several clonal expansion events. First, the expansion of specific T
lymphocytes against the antigen (T H1, T H17 or T H2). Second, the expansion of HF T lymphocytes. Thirdly,
the expansion of B lymphocytes in their first phase. Finally, clonal expansion of B lymphocytes takes place
in the germinal center. Swollen nodes may become apparent on clinical examination.
B lymphocytes remature in the germinal center and do so simultaneously with clonal expansion. Remember
that the maturation of B lymphocytes happens mostly in the bone marrow, to give rise to virgin B
lymphocytes. After the recognition of the antigen, its activation and the formation of the germinal center,
the B lymphocytes undergo a new maturation process. This process aims for B lymphocytes to mature
against the pathogen they are attacking. Maturation consists of gene recombinations that promote isotype
change and affinity maturation.
The isotype change consists of a change of the constant region of the BCR heavy chain (regions C H1-3 ) so
that the IgM isotype of the BCR becomes IgG, IgE or IgA. In addition, secreted antibodies also change their
constant regions. The antibody isotype chosen depends on the cytokines present in the ganglion. These
cytokines are those secreted by the profile of T lymphocytes that have expanded in the ganglion against the
same pathogen. Specifically:
- If it is an H1-type response to extracellular bacteria, H1 T cells secrete the cytokine IFN-γ (interferon-γ).
This cytokine is present in abundance in the ganglion and reaches the B lymphocytes of the germinal
center to induce the change of isotype to IgG. As we will explain in Chapter 14, IgG is the most effective
antibody against these pathogens.
- If it is a T-type H2 response to a helminth, H2 T cells secrete the cytokine IL-4. This cytokine, present
mostly in the ganglion, reaches the B lymphocytes of the germinal center and induces the change of
isotype to IgE.
- In the mucous membranes, the presence of REG T lymphocytes (regulatory T) makes the majority
cytokine TGF-β (tissue growth factor β). This cytokine reaches the B lymphocytes and induces the
change of isotype to IgA, compared to commensals of the mucous membranes.

The molecular mechanism that explains the isotype change is gene recombination. The BCR heavy chain
gene contains the exons of the constant regions ordered as follows: constant of M (Cμ), constant of G (Cγ),
constant of E (Cɛ) and constant of A (Cα). During recombinations, a loop is formed that forces the approach
of the exon Cμ to one of the exons Cγ, Cɛ or Cα. The size of the loop to favor one or the other approach
depends on the cytokines present in the germinal center.

- If the change is from IgM to IgG, the cytokines present induce the recombination of the Cμ regions with
Cγ in order to express the Cγ region.
- If the change is from IgM to IgE, the cytokines present induce the recombination of the regions of Cμ
with Cɛ in order to express the Cɛ region.
- If the change is from IgM to IgA, the cytokines present induce the recombination of the regions of Cμ
with Cα in order to express the Cα region.

Change of isotype of antibodies.


(a) In the constant region of the BCR genes are located the
exons of the constant regions of different isotypes of
immunoglobulins: Cμ for IgM, Cγ for IgG, Cα for IgA and Cɛ for
IgE. (b-d) For the isotype change, a loop is formed by which Cμ
approaches the different exons Cγ, Cα and Cɛ. Depending on
the cytokines present, the loop is smaller or larger. The exon
that is expressed determines the isotype of antibody that is
generated, which is IgM prior to the change of isotype and IgG
(b), IgA (c) or IgE (d), depending on the size of loop that is
formed.

Affinity maturation consists of converting the variable regions of the BCR light chain into regions of higher
affinity towards the pathogen antigen. This process happens in two parts:
- Somatic hypermutation: consists of a series of mutations on the variable region of the BCR, allowed in
the dark zone of the germinal center.
- Selection of high-affinity B lymphocytes: through selection, dendritic cells interact with high-affinity B
lymphocytes and promote their survival. This selection is carried out by special dendritic cells called
follicular dendritic cells, located in the clear area of the germinal center. Dendritic cells retain the
antigen on their surface by phagocytic receptors and show it to B lymphocytes. B lymphocytes have two
fates:
o B cells with hypermutated BCR that bind to dendritic cells survive.
o B cells with hypermutated BCR that do not bind to dendritic cells die.
At the end of the immune response, when there is little antigen left, it is retained on the surface of
dendritic cells and B lymphocytes must compete to bind to the antigen. In this situation, only B
lymphocytes with higher affinity BCRs survive.

GENERATION OF PLASMA CELLS AND MEMORY B LYMPHOCYTES


B lymphocytes that undergo the change to the appropriate isotype and are selected as high-affinity B
lymphocytes differentiate into long-lived plasma cells or memory B lymphocytes. Plasma cells generate
high-affinity antibodies for almost a lifetime, while memory B lymphocytes will do so against a pathogen in
a second or successive exposures to it. Both types of B lymphocytes are responsible for the immunological
memory of B lymphocytes.
After an unknown infection, the doctor can know the type of causative pathogen based on the type of
major antibody present in the patient's serum. For example, abundant levels of IgG may indicate infection
with viruses or phagocytic bacteria, while elevated levels of IgE may indicate helminth infection.

RECOGNITION AND ACTIVATION OF B LYMPHOCYTES 1 AND B 2ZM


The recognition of antigen, and, therefore, the activation of B lymphocytes 1 and B 2ZM, is different from
what was explained above.
Antigens activate these lymphocytes directly. To do this, they must be multivalent antigens with identical
repeated epitopes. They are usually polysaccharides or lipids, since both types of molecules have identical
units that are repeated. They are not usually proteins.

The binding of these antigens to the BCR of B 1 and B 2ZM lymphocytes induces their activation. This is
because the multivalent binding to several BCR molecules of the same B cell is strong enough to induce B
cell activation. This type of B cell activation does not always require warning from the innate immune
system. In addition, remember that B 1 lymphocytes and 2ZM B lymphocytes have not very diverse
receptors that only recognize frequent antigens. Their low diversity together with their independence from
the innate immune system makes these B lymphocytes considered similar to cells of the innate immune
system.
The activation of B 1 lymphocytes and 2ZM B lymphocytes triggers the following processes:

1. Clonal expansion.
2. Secretion of low-affinity IgM antibodies.
3. Formation of short-lived plasma cells.

These B lymphocytes do not form germinal centers or memory B lymphocytes.


B lymphocytes 1 and B 2ZM are very efficient against certain pathogens that surround themselves with a
polysaccharide capsule as a mechanism of evasion of the immune system. Examples of these pathogens are
Neisseria meningitidis, Haemophilus influenzae or Streptococcus pneumoniae. This capsule surrounds the
pathogen hiding its pathogen-associated molecular patterns (PAMP) and antigens. B 1 and B 2ZM
lymphocytes are the only ones capable of recognizing the capsule, as they can identify multivalent antigens
of the polysaccharide. Upon recognizing the capsule, B lymphocytes are activated and secrete IgM
antibodies against the pathogen and cause its elimination.
There is a special type of antibodies generated by B 1 and B 2ZM lymphocytes. They are called natural
antibodies. Natural antibodies are generated without the need for the BCRs of B lymphocytes to recognize
any antigen. They are formed in the first years of life and last all of it. All individuals possess them. Natural
antibodies are characterized by the following:
- They are of low affinity IgM isotype.
- They can recognize:
o Pathogens.
o Erythrocytes (specifically the molecules responsible for the blood groups of the AB0 system).
o Apoptotic cells.
o LDL (low-density lipoproteins) oxidized.

Its function, therefore, is immunological but also homeostatic, that is, to maintain the proper functioning of
the organism. In particular, natural antibodies against erythrocytes are very important in blood transfusions
or organ transplants.

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